Objectives: To investigate the plasma concentrations of lecithin:cholesterol acyltransferase (LCAT EC 2.3.1.43) and erythrocyte membrane Na+,K+,ATPase and the correlation of these parameters in diabetes mellitus. Design and Methods: Na+,K+,ATPase was measured with spectro-photometric method and LCAT with radioactive method in 19 patients with insulin-dependent diabetes mellitus (IDDM), in 20 with non-insulin-dependent diabetes mellitus (NIDDM) and in 20 healthy volunteers as the control group. Results: Compared with the control group, plasma LCAT concentrations were found to be decreased in both of the patient groups (p < 0.01 for both). Erythrocyte membrane Na+,K+,ATPase activities were higher in the controls than both in the NIDDM and IDDM groups (p < 0.01 and p < 0.001, respectively). There were significant correlations between LCAT and Na+,K+,ATPase in IDDM (r = 0.82, p < 0.001) and in NIDDM (r = 0.74, p < 0.001). In order to investigate the effect of cholesterol (C) and lysophosphatidylcholine (LPC) on Na+,K+,ATPase activity, this enzyme's activity was determined in erythrocyte membranes obtained from diabetic subjects after in vitro incubation with increasing concentrations of LPC and C (2-10 mu M). Enzymatic activity was significantly reduced by in vitro C at increasing concentrations but significantly increased by in vitro LPC at increasing concentrations. Conclusions: From these data, it is to be concluded that the decrease in Na+,K+,ATPase activity in diabetes might be due to decreased LCAT concentrations and that may explain the development of atherosclerosis in diabetics.